Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic alpha cells

Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix, and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycemia and its oversecretion at high blood glucose ...

2型糖尿病（Type 2 diabetes mellitus, T2DM）的发生与胰岛素抵抗及胰岛β细胞（β-cells）随疾病进展无法合成并分泌足量胰岛素密切相关。然而，仅以胰岛素分泌与作用为靶点的临床治疗方案收效有限。因此，研究焦点逐渐转向胰岛α细胞（α-cells），尤其是其胰高血糖素（glucagon）分泌失调的异常表现。我们基于电子显微镜的定性观察结果显示，西式饮食诱导的T2DM模型中，α细胞内的线粒体存在结构异常。具体而言，从小鼠胰腺组织中分离提取的α细胞呈现出线粒体密度降低、线粒体基质（mitochondrial matrix）表达减弱以及线粒体嵴（cristae）数量减少的特征。此类线粒体超微结构（mitochondrial ultrastructure）的异常提示线粒体ATP生成效率下降，这促使我们从理论层面探索并阐明T2DM相关的最具挑战性的问题之一：即低血糖（hypoglycemia）状态下胰高血糖素分泌不足，而高血糖（high blood glucose）状态下却过度分泌……